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October 18, 2009
8:00 AM - 9:30 AM
Room Room 356
Inhaled Anesthetics Differentially Affect Neurotransmitter Release between Various CNS Regions
  **   Hugh C. Hemmings, M.D., Ph.D., No-Bong Kwok, B.S., Robert I. Westphalen, Ph.D.
Anesthesiology, Weill Cornell Medical College, New York, New York
Introduction: Inhaled anesthetics (IAs) inhibit 4-aminopyridine (4AP)-evoked release of the excitatory transmitter glutamate with greater potencies than release of the inhibitory transmitter GABA (1). Transmitter release evoked by 4AP, a secretogogue that mimics action-potential stimulation of release, requires activation of voltage-gated Na + and Ca 2+ channels (2), consistent with a role for presynaptic Na + channels in the effects of IAs. The hypothesis that IAs affect the release of various neurotransmitters by nerve terminal-specific presynaptic mechanisms was explored by comparing the effects of IAs on glutamate and GABA release from 4 neurochemically distinct regions of the rat CNS.

Methods: Isolated nerve terminals prepared from adult male SD rat cerebrocortex (Cx), hippocampus (Hip), striatum (Str) and spinal cord (SC) according to NIH guidelines were prelabeled with [ 3 H]glutamate and [ 14 C]GABA and superfused at 37 o C (1), and release was evoked by a 2 min pulse of 1 mM 4AP in the presence or absence of isoflurane, halothane, or the Na + channel antagonist tetrodotoxin (TTX). Release was quantified as summed fractional release above baseline. Concentration-effect data were fitted to sigmoidal curves and differences between IC 50 values were determined by F-test comparisons of best-fit values derived from independent curve fits.

Results: Isoflurane and halothane showed selective inhibition of glutamate vs. GABA release in Cx and Hip, less selectivity in Str, and no selectivity in SC (Figure). TTX inhibited glutamate and GABA release with different potencies between CNS regions and between transmitters of the same CNS region. Sensitivity of glutamate or GABA release to IAs did not correlate with sensitivity to inhibition by TTX across the 4 CNS regions.

Conclusions: The relative potencies for inhibition of glutamate and GABA release by IAs and TTX varied significantly between CNS regions, consistent with region-specific differences in anesthetic mechanisms. Preferential inhibition of glutamate vs. GABA release is evident in Cx, Str and Hip, but not in spinal cord; the greater sensitivity of SC release to isoflurane is consistent with a role for presynaptic actions in immobilization which is mediated in the SC (3). Varied sensitivities of transmitter release could result from differential expression of Na + and/or Ca 2+ channel subtypes and/or other presynaptic anesthetic targets. Varied TTX sensitivities between CNS regions support differential expression of Na v isoforms with distinct properties, regulation, and/or density. Comparing Na v isoform distribution with release inhibition might illuminate a role for nerve terminal-specific differences in presynaptic targets in the differential effects of IAs on transmitter release.

References: 1. Westphalen & Hemmings (2006) JPET 316: 216-223; 2. Tibbs et al. (1989) J Neurochem 53: 1693-1699; 3. Eger et al. (1997) Anesth Analg 84: 915-918

Supported by NIH grant GM 58055.[figure1]

From Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists.
Figure 1